NEUROPATHOLOGY- MUSCLE DISEASES

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I. MUSCLE BIOPSY
II. SITE OF MUSCLE BIOPSY
III. ANATOMY, PHYSIOLOGY AND BIOCHEMISTRY
IV. DIAGNOSIS OF MUSCLE DISEASE
V. PATHOLOGIC CHANGES OF MUSCLE
VI. SPECIFIC MUSCLE DISEASES

VOCABULARY TERMS
Terms you should be familiar with:

Histochemistry
Neuromuscular junction
T tubules
Sarcoplasmic reticulum
Myotonia
Electromyogram
Creatine kinase
Myopathic
Neurogenic
Atrophy
Hypertrophy
Fiber type predominance
Fiber type deficiency
Fiber type grouping
Ragged red fibers
Muscular dystrophy
Duchenne muscular dystrophy
Myotonic dystrophy
Polymyositis
Dermatomyositis
Myasthenia gravis

OBJECTIVES: The objectives of this hour are to gain an appreciation of the normal anatomy and physiology of muscle, to understand the indications for muscle biopsy, to review the history and physical findings in patients with muscle disease, to distinguish between myopathic and neurogenic disease of muscle, and to consider four major diseases of muscle.

I. MUSCLE BIOPSY

Routine histochemistry performed on frozen sections.

II. SITE OF MUSCLE BIOPSY

• When possible choose muscle actively involved in the disease process.
  
  
• Do not sacrifice clinical involvement for surgical availability.
  
  
• Avoid sites that have been traumatized (previous biopsies, injection sites, etc.).
  
  
• Avoid severely atrophic or fibrotic muscles. End stage muscle disease is unlikely to yield diagnostic information.
  
  
• Avoid needle biopsies.
  
  
• Insist on clinical history, and physical and electrodiagnostic findings.

III. ANATOMY, PHYSIOLOGY AND BIOCHEMISTRY

• Skeletal muscle is characterized by being voluntary, paired (i.e. agonist and antagonist), fusiform in shape with tendon insertions and striated.
  
  
• Cross sectional muscle is organized into several fascicles containing variable numbers of individual fibers (cells). Each muscle cell is multinucleated and the nuclei are located in the peripheral part of the cell.
  
  
• Energy Sources
  
  
  • Oxidative (aerobic): type I fibers
  • Glycolytic (anaerobic): type II fibers
    
    
• Information Transmission
  
  
  • Neuromuscular junction
  • T tubules and sarcoplasmic reticulum
    
    
• Associated Tissue
  
  
  • Connective tissue
  • Fat
  • Blood vessels
  • Peripheral nerves

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IV. DIAGNOSIS OF MUSCLE DISEASE

(Essentially the differential diagnosis of weakness)

• History (Symptoms)
  
  
  • Duration
  • Family and genetic history
  • Progressive or with remission
  • Painful or painless
    
    
• Physical Examination (signs)
  
  
  • Degree of weakness
  • Extent and location of weakness
  • Reflexes
  • Myotonia
  • Consistency and palpation
    
    
• Laboratory Tests
  
  
  • Electromyogram (EMG)
  • Serum enzymes, especially creatine kinase (CK).
  • Muscle biopsy- histology, histochemistry, electron microscopy (if needed)

V. PATHOLOGIC CHANGES OF MUSCLE

Diseases affecting muscle can be divided into two large categories, myopathic (primary or intrinsic to the muscle) and neurogenic (secondary or extrinsic to the muscle, usually due to diseases of peripheral nerves or the anterior horn cell). The pathologic changes found in a particular muscle disease are combinations of the descriptions that follow and dependent on the exact nature of the disease.

• Changes in Fiber Size
  
  
  • Atrophy- may be uniform or selective (i.e., small group, large group, or perifascicular atrophy)
  • Hypertrophy- may be uniform or selective
    
    
• Abnormalities of Fiber Distribution
  
  
  • Fiber type predominance
  • Fiber type deficiency
  • Fiber type grouping (pathognomonic of neurogenic disease)
    
    
• Changes in Fiber Nuclei
  
  
  • Internal nuclei (usually seen in myopathic disease)
  • Nuclear clumps
  • Vesicular nuclei (regeneration)
  • Pyknotic nuclear clumps
    
    
• Fiber Degeneration and Regeneration
  
  
  • Fiber splitting
  • Sarcoplasmic hyaline masses
  • Phagocytosis
  • Granular or ragged red fibers
  • Regenerating fibers
    
    
• Cellular Reactions
  
  
  • Inflammatory infiltrates
  • Fibrosis
    
    
• Changes of Fiber Architecture
  
  
  • Target fibers
  • Central cores
  • Ring fibers
  • Rod or nemaline bodies
  • Ultrastructural abnormalities
    
    
• Changes of Muscle Suggesting Neurogenic Disease
  
  
  • Group atrophy
  • Vesicular nuclei
  • Atrophic fibers of both I and II
  • Fiber type grouping
  • Target fibers

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VI. SPECIFIC MUSCLE DISEASES

There are a wide variety of muscle diseases including the muscular dystrophies, congenital myopathies, metabolic and endocrine myopathies inflammatory myopathies, those of the myoneural junction, and neurogenic. Time will allow for discussion of a few, but important, examples.

• Duchenne Muscular Dystrophy
  
  
  • X linked recessive. Most common childhood onset form of muscular dystrophy. Affects 1 in 3,500 live male births. 1/3 of cases = new mutations
    
    
  • Onset of symptoms at about 1 year of age. Delayed motor development (late walking) and proximal muscle weakness
    
    
  • Death about age 20 due to respiratory muscle weakness with resultant infection
    
    
  • Characteristic pseudohypertrophic calves
    
    
  • Creatine kinase very high
    
    
  • Severe myopathic features on muscle biopsy with prominent variability of muscle fiber size and shape, severe fiber degeneration and regeneration, and a marked increase in connective tissue around muscle fibers
    
    
  • Etiology is linked to severe deficiency or absence of dystrophin related to genetic defect of Xp21 (largest known gene, 1.5% of entire X chromosome). The genetic defect is most often a deletion ranging from a few kb to 4 Mb. Exact biologic function of dystrophin is unknown. In muscle it is thought to link cytoskeleton to extracellular matrix for added strength and rigidity of muscle membrane. Linkage to extracellular matrix may help dissipate the forces of contraction by transmitting them to the surrounding connective tissue. Without dystrophin the sarcolemma receives far greater forces, leading to tears in the membrane, loss of structural integrity, calcium leakage into sarcoplasm, and activation of proteolysis.

  
  

• Myotonic Dystrophy
  
  
  • Autosomal dominant with characteristic marked variable expression. This represents one of the"trinucleotide repeat"diseases
  • Characteristic myopathic facies often present
  • Weakness often more severe distally
  • Myotonia usually present
  • Systemic involvement seen with cataracts, frontal balding, testicular atrophy, cardiac conduction blocks, hypersomulence, mental retardation, hypercatabolism of IgG, peripheral insulin resistance, and much more
  • Muscle pathology shows marked increase in numbers of internal nuclei, selective atrophy of type I muscle fibers, subsarcolemmal pads, and ring fibers.
    
    
• Inflammatory Myopathies
  
  
  • Polymyositis
    • Progressive proximal weakness often associated with severe neck flexor weakness and dysphagia
    • Pathology shows prominent inflammatory response within the muscle.
    • Studies would suggest that the pathogenesis of polymyositis is related to an auto destructive immune response, i.e. the immune system seems to be turned on against muscle.
  • Dermatomyositis
    • Progressive proximal weakness and rash
    • Pathology, particularly in younger individuals, often shows characteristic perifascicular atrophy
    • Studies would suggest that the pathogenesis of dermatomyositis is related to a vasculopathy, particularly involving capillaries and occasionally small arterioles
    • Strong association with systemic carcinoma
  • Inclusion body myositis
    
    
• Myasthenia Gravis
  
  
  • Symptoms and signs
    • Ocular involvement results in ptosis and diplopia and occurs in 90% of cases
    • Bulbar involvement results in dysarthria and dysphagia
    • Classically fatigable weakness
    • Classically diurnal variation in strength, i.e. best in morning, worse as the day progresses
  • Pathophysiology
    • Autoimmune response against the acetylcholine receptor resulting in a decreased number of available receptors
    • Antibodies against receptors found in 85% of cases
  • Diagnosis
    • Tensilon test
    • Repetitive stimulation on EMG
    • Receptor antibody titer in serum
  • Treatment
    • Anticholinesterase
    • Thymectomy
    • Immunosuppression
    • Plasmapheresis

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Go Back to Course Outline

Go Back to Neuropathology

[ Introduction and Objectives | Basic Reactions of the CNS | Vascular Disease | Trauma to the CNS | Alcohol and the CNS | Infections of the CNS | Tumors of the CNS | Diseases of the Myelin Sheath | Spinal Cord Disease | Muscle Disease | Congenital Anomalies of the CNS | Neuropathology of AIDS | Degenerative Diseases of the CNS | Dementia and Related Issues | Unconventional Transmissible Agent (Prion) Diseases ]

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